SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer.

Cancer cells modulate their metabolic activities to adapt to their growth and proliferation. Despite advances in breast cancer biology having led to the widespread use of molecular targeted therapy and hormonal drugs, the molecular mechanisms in metabolism related to the regulation of breast cancer cell proliferation are still poorly understood. Here, we investigate the possible role of SHMT2, a key enzyme in serine metabolism, in breast cancer. Firstly, SHMT2 is found highly expressed in both breast cancer cells and tissues, and patients with high expression of SHMT2 have a worse prognosis. Moreover, the intervention of SHMT2 by either knockdown or over-expression in vitro induces the effect on breast cancer proliferation. Mechanistically, RNA-seq shows that over-expression of SHMT2 affect multiple signaling pathways and biological process in breast cancer cells. Furthermore, we confirm that SHMT2 promotes breast cancer cell growth through MAPK and VEGF signaling pathways. Finally, we verify the role of SHMT2 in promoting breast cancer growth in the xenograft tumor model. Our results indicate that SHMT2 plays a critical role in regulating breast cancer growth through MAPK, and VEGF signaling pathways, and maybe serve as a therapeutic target for breast cancer therapy.

Expression of PD-1/PD-L1 in head and neck squamous cell carcinoma and its clinical significance.

OBJECTIVE: To investigate the role of programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and P16 in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: A total of 95 paraffin-embedded samples of tumorous tissue of HNSCC were collected. Expression levels of PD-1, PD-L1, and P16 were determined by immunohistochemistry. RESULTS: A significantly higher proportion of PD-1 among patients infected with the human papillomavirus was found. PD-L1 expression is closely associated with the primary site of the tumor, postoperative recurrence, survival, PD-1 expression and P16 expression. Univariable analysis indicated that T stage, N stage, tumor node metastasis stage, tumor differentiation, and PD-L1 expression were all shown to be prognostic variables for overall survival in patients with HNSCC. In the multivariate analysis, only N stage (P = 0.010) and PD-L1 expression (P = 0.001) were found to be independent prognostic variables for overall survival. In addition, for disease recurrence, multivariate analysis showed that only PD-L1 expression was the associated independent risk factor. For the patients with negative PD-L1 expression, Kaplan-Meier analysis revealed that they had significantly worse outcomes in terms of overall survival (P = 0.001). Similarly, compared with the patients with positive PD-L1 expression, those with negative PD-L1 expression had a higher probability of recurrence (P = 0.026). CONCLUSIONS: The expression of PD-L1, PD-1, and P16 in HNSCC is significantly correlated. Human papillomavirus infection (P16 positive) is negatively related to postoperative recurrence. HNSCC patients with positive PD-L1/PD-1 expression tend to have better overall survival outcomes and lower probability of recurrence, providing more evidence for the PD-l-targeted immunotherapy of HNSCC.

Significant prognostic impact of chemoradiotherapy-induced hemoglobin decrease on treatment outcomes of nasopharyngeal carcinoma.

PURPOSE: To investigate prognostic impact of chemoradiotherapy-induced hemoglobin (Hb) decrease on treatment outcomes of endemic nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Eight hundred and fifteen non-metastatic NPC, receiving neoadjuvant chemotherapy followed by radiotherapy (NACT+RT group) or concomitant chemoradiotherapy (CCRT group), were enrolled in this study, who were regrouped according to pre-radiotherapy Hb (pre-RT Hb), post-radiotherapy Hb (post-RT Hb) and individual Hb decrease through radiotherapy or CCRT (△Hb), respectively. Survival curves were estimated using Kaplan-Meier method and compared by log-rank test. Multivariate analysis was performed using the COX proportional hazard model and binary logistic regression model. RESULTS: A poorer 5-year disease-free survival (DFS) was observed when pre-RT Hb<130.00 g/L. However, post-RT Hb<130.00 g/L was associated with significantly poorer 5-year locoregional recurrence-free survival (LRFS) (P=0.010) and disease specific survival (DSS) (P=0.008). Multivariate analysis with the COX proportional hazard model identified post-RT Hb<130.00 g/L as an independent negative prognostic factor for both LRFS (hazard ratio [HR], 1.896; 95% confidence interval [CI], 1.158-3.106; P=0.011) and DSS (HR, 1.767; 95% CI, 1.152-2.711; P=0.009). Similarly, △Hb <-15.00 g/L also predicted poorer 5-year LRFS (P=0.024) and DSS (P=0.015), which was confirmed in multivariate analysis as an independent adverse prognostic factor for LRFS (HR, 1.586; 95% CI, 1.058-2.377; P=0.026) and DSS (HR, 1.556; 95% CI, 1.087-2.227; P=0.016), respectively. Multivariate analysis with binary logistic regression model indicated that CCRT was a significantly independent predictor for post-RT Hb <130.00 g/L and △Hb < -15.00 g/L. CONCLUSIONS: Chemoradiotherapy-induced decreased Hb levels have negative influence on locoregional control and survival, and might counteract the benefit of neoadjuvant/concomitant chemotherapy. Further studies on supportive care to maintain sufficient Hb level during chemo-radiotherapy are warranted.